tbuckley/cabot-search huggingface dataset:
Abstract 6246: WNT signaling-mediated <i>DKC1</i> expression drives stemness associated with colorectal cancer
Authors: Shivansh Nigam, Ayush Praveen, Bushra Ateeq
Journal: Cancer Research (2022)

Abstract The emergence of subclonal mutations in high grade colorectal (CRC) tumors driving resistance against EGFR targeting is a major challenge, thus necessitating the discovery of alternative therapeutic strategies. Targeting aberrantly active WNT signaling provides an alternate route for CRC treatment. Here we show that the high DKC1 expression in CRC patients associates with advanced-stage disease regardless of RAS/RAF mutation status, indicating the potential of DKC1 as a pan-CRC therapeutic target. We show a direct regulation of DKC1 downstream of canonical WNT signaling and confirm it as one of the WNT targets. Mechanistically, DKC1 regulates several critical cellular processes such as telomere maintenance, pseudouridylation of ribosomal RNAs, ribosomal biogenesis, etc. However, its plausible association with cancer stemness remains largely unexplored. We generated stable DKC1 knockdown (DKC1-KD) cell lines, namely WiDr and Colo320HSR to investigate its role in cancer stemness and CRC progression. DKC1-KD cells show a significant reduction in the tumor sphere forming ability along with diminished cell surface expression of stemness markers. Using multiple publicly available gene expression datasets for CRC patients, we performed Gene Set Variation Analysis to characterize the association of DKC1 with upregulated gene signature of consensus molecular subtype 2 (CMS2) of CRC, which has been associated with the highest incidence rate and active WNT signaling. Further, Database for Annotation Visualization and Integrated Discovery tool-based analysis across these CRC patient samples striated based on DKC1 expression shows positive enrichment of biological processes related to cell cycle regulation. Consistently, we observed a G2/M phase cell cycle arrest upon silencing DKC1 in CRC cells. We also show that silencing DKC1 results in enhanced chemosensitivity with a remarkable reduction in lipid accumulation. Moreover, upon DKC1 silencing, an increase in epithelial marker E-cadherin and a decrease in mesenchymal marker N-cadherin expression was observed, suggesting its role in epithelial-to-mesenchymal transition (EMT) in CRC. Our findings demonstrate the role of DKC1 in regulating stemness, drug resistance, and EMT to drive CRC oncogenicity. Taken together, we highlight the role of DKC1 as the most suitable pan-CRC drug target by employing the potential of pharmacological inhibitors against WNT signaling. Citation Format: Shivansh Nigam, Ayush Praveen, Bushra Ateeq. WNT signaling-mediated DKC1 expression drives stemness associated with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6246.
Abstract 1941: Accurate pan-cancer tumor purity estimation from gene expression data
Authors: Egor Revkov, Ken W.-K. Sung, Anders J. Skanderup
Journal: Cancer Research (2022)

Abstract Tumors are complex masses composed of malignant and non-malignant cells. Variation in tumor purity (malignant cell fraction) can both confound integrative analysis and enable studies of tumor heterogeneity. Here we developed PUREE, which uses a weakly supervised learning approach to infer tumor purity from a tumor gene expression profile. PUREE was trained on gene expression data and genomic consensus purity estimates from approximately 8000 solid tumor samples. Using a linear model based on 170 input genes, PUREE predicted purity with high accuracy across distinct solid tumor types and generalized to tumor samples from unseen tumor types. PUREE input genes features were further validated using single-cell RNA-seq data from distinct tumor types. In a comprehensive benchmark, PUREE outperformed all existing transcriptome-based purity estimation approaches. We also show that the accuracy of a pan-cancer model is comparable to models optimized for individual tumor types, highlighting compositional properties of the tumor microenvironment conserved across tumor types. Overall, PUREE is a highly accurate and versatile method for estimating tumor purity and interrogating tumor heterogeneity from bulk tumor gene expression data. Citation Format: Egor Revkov, Ken W.-K. Sung, Anders J. Skanderup. Accurate pan-cancer tumor purity estimation from gene expression data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1941.
Abstract 1819: CBP-1008 shows excellent efficacy and desirable drug safety profile in preclinical models
Authors: Wei Tan, Wei Wang, Tingting Bu, Xuelian Liu, Yan Teng, Baohua Huang
Journal: Cancer Research (2022)

Abstract Folate Receptor Alpha (FRα) is the high affinity folate transporter which is highly expressed in ovarian, lung and breast cancer. Transient Receptor Potential Vanilloid 6(TRPV6), a calcium channel characterized by its high calcium selectivity. It plays an important role in calcium absorption in small intestine and calcium uptake in other epithelial tissues. TRPV6 is also upregulated in breast, ovarian and prostate cancer. CBP-1008, A first-in-class drug conjugate which targets both FRα and TRPV6 with low molecular-weight ligands has been developed. CBP-1008 binds to FRα with high affinity and TRPV6 with low affinity. In presence of TRPV6, CBP-1008 shows faster FRα-mediated internalization and cytotoxicity than it does in absence of TRPV6. Systemic clearance CBP-1008 is observed within 6 hrs. However, the drug retained and accumulated in tumors with a half-life over 48 hrs. As a result, CBP-1008 shows excellent efficacy on tumors with target expression and the response is durable. MTD of CBP-1008 reaches 4 mg/kg in mice, 2 mg/kg in rat and 1 mg/kg in monkey. During the development of molecularly-targeted therapeutics, biomarker assays which can stratify patients and enrich those who respond well to the therapy, play a very critical role. We generated an anti-TRPV6 antibody and developed a first-in-class IHC-based TRPV6 assay. This assay along with an FRα IHC assay have been validated per CAP/CLIA guidelines for patient selection in our clinical trials. Intended indications including ovarian cancer, endometrial cancer, breast, NSCLC and pancreatic cancer. We have evaluated a panel of ovarian PDX models for their biomarker expression and response to CBP-1008 to determine their correlation. It is found that FRα+/TRPV6+ tumor responds better than tumors which have at least one marker negative. Within the FRα+/TRPV6+ tumors, tumor growth inhibition well correlates with IHC score of FRα (R2=0.89). It is indicated that clinical trials in selected indications using biomarkers assay to screening patients will expedite the clinical development of CBP-1008. Initial clinical response has been observed in our Phase I trial. Citation Format: Wei Tan, Wei Wang, Tingting Bu, Xuelian Liu, Yan Teng, Baohua Huang. CBP-1008 shows excellent efficacy and desirable drug safety profile in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1819.
Abstract 3053: Using individual or a consortium of bacteria for immuno-oncology research
Authors: Sylvie Maubant, Marie Leblanc, Elisabeth Bertrand, Audrey Bertaux, Loic Morgand, Maxime Ramelet, Marie Lux, Olivier Duchamp, Fabrice Vivani
Journal: Cancer Research (2022)

Abstract Preclinical and clinical studies have shed light on the beneficial role of bacteria for cancer therapy. Indeed, these studies have demonstrated that these microorganisms have beneficial properties that allow them to selectively colonize tumor and that they could also be considered as predictive drug efficacy biomarkers. Based on these results, bacteria are now used for delivering therapeutic components or for shaping the gut microbiota. Ultimately these approaches lead to the activation of an immune response against the tumor. Owing to our scientific and technological expertise in manipulating microbes, we propose tailor-made strategies for investigating the efficacy of bacteria-based treatments and/or the effect of therapies on the microbiota both in vitro and in vivo. Different methods/analyses can be used for culturing, detecting, quantifying, identifying and localizing live bacteria (e.g. counting of CFUs, PMA-qPCR, 16 rRNA gene sequencing, mass spectrometry, bioluminescence) in simple or complex samples (e.g. from culture of single bacterial species to rodent/human stools or other tissues). In addition, a continuum of assays allows us to evaluate the impact of bacteria or derived products directly on tumor and/or immune cells (e.g. immune infiltrate and phenotyping, cytokine/chemokine profiling, tumor burden). We will highlight some results obtained in a cancer context such as the immunostimulatory properties of bacteria or their derivatives, the selective colonization of tumor tissue by bacteria, the benefits in delivery of therapeutic proteins or antigens by bacteria, the impact of tumor engraftment/growth on gut microbiota, the effects of chemotherapeutic agents on intestinal microflora, the consequences of supplementation with bacteria or antibiotics treatment on the response to immune checkpoint inhibitors. Altogether these data demonstrate that bacteria are now allies in the treatment of cancer and that our comprehensive platform is suitable for evaluating both in vitro and in vivo therapeutics developed from bacteria (individuals, consortium or derived products; native or modified). All these technologies can be also applied to develop novel therapeutic strategies for inflammatory and infectious diseases known to increase the risk of cancer development. Citation Format: Sylvie Maubant, Marie Leblanc, Elisabeth Bertrand, Audrey Bertaux, Loic Morgand, Maxime Ramelet, Marie Lux, Olivier Duchamp, Fabrice Vivani. Using individual or a consortium of bacteria for immuno-oncology research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3053.
Abstract 2623: Variants of CLIP-170 associated with taxane resistance in tumors
Authors: Prashant V. Thakkar, Katsuhiro Kita, Urko del Castillo, William G. Stone, Giuseppe Galletti, Neel Madhukar, Elena Vila Navarro, Elena Barasoain, Holly V. Goodson, Dan Sackett, José Fernando Díaz, Yao Lu, Arindam RoyChoudhury, Henrik Molina, Olivier Elemento, Manish A. Shah, Paraskevi Giannakakou
Journal: Cancer Research (2022)

Abstract Despite its widespread use, the majority of patients with gastric cancer (GC) will not respond to taxane chemotherapy due to resistance mechanisms. Recently, we reported the discovery of a novel truncated variant of the microtubule plus-end binding protein CLIP-170, hereafter CLIP-170S, whose expression is enriched in taxane resistant cell lines and patients with GC. Mass-spec proteomics and 5’-RACE further showed that CLIP-170S lacked the first 155 amino acids, including the Cap-Gly motif required for microtubule plus-end localization. CLIP-170S knockdown reversed taxane resistance in cells and xenografts, whereas its re-expression led to resistance, suggesting causation. Unlike canonical CLIP-170, we showed that CLIP-170S was mislocalized from the MT plus-end to the MT lattice. Computational analysis of RNA-seq data in conjunction with the connectivity map from taxane-sensitive and resistant GC cell lines, predicted imatinib as the top candidate drug to overcome drug resistance. Imatinib treatment completely reversed taxane resistance, as predicted, and did so unexpectedly by selective depletion of CLIP-170S. Other RTK inhibitors also depleted CLIP-170S, suggesting a class effect. We are currently unraveling the molecular mechanisms by which a) CLIP-170S impairs taxane association to its microtubule binding site and b) Imatinib and other RTK inhibitors selectively deplete CLIP-170S. Our data show that CLIP-170S is a clinically prevalent variant that confers taxane resistance in tumors, whereas the discovery of Imatinib as a CLIP-170S inhibitor provides novel therapeutic opportunities for future trials. Citation Format: Prashant V. Thakkar, Katsuhiro Kita, Urko del Castillo, William G. Stone, Giuseppe Galletti, Neel Madhukar, Elena Vila Navarro, Elena Barasoain, Holly V. Goodson, Dan Sackett, José Fernando Díaz, Yao Lu, Arindam RoyChoudhury, Henrik Molina, Olivier Elemento, Manish A. Shah, Paraskevi Giannakakou. Variants of CLIP-170 associated with taxane resistance in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2623.
Abstract 5400: Detection of satellite tumor cells in peritumoral edema in myxofibrosarcoma and undifferentiated pleomorphic sarcoma using targeted gene sequencing
Authors: Miguel Alfonso V. Principe, Nalan Gokgoz, Patrick Prochazka, Peter C. Ferguson, Simin Dewji, Jay S. Wunder, Irene A. Andrulis, Brendan C. Dickson, Kim M. Tsoi
Journal: Cancer Research (2022)

Abstract Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcomas (UPS) are soft tissue sarcomas with high local recurrence rates following resection. Common with these cancers is peritumoral edema, termed tumor tails, which our group has found could contain satellite tumor cells. A precise and accurate method of determining the presence of satellite tumor cells in this region is required to improve surgical planning, as the standard morphology-based technique is prone to misclassification. An emerging technology is targeted gene sequencing (t-NGS), a combination of whole genome or exome sequencing (WGS/WXS) comparing primary tumor and patient-matched blood, and digital droplet PCR (ddPCR). The objective of this study was to determine the viability of t-NGS in the detection of satellite tumor cells in the areas of edema surrounding MFS and UPS. A cohort of patients diagnosed with extremity MFS and UPS at Mount Sinai Hospital (Toronto, Canada) who underwent resection were retrospectively studied. Cases with available WGS/WXS data were used (n=8) to identify case-specific tumor-specific variants (TSV) to detect with the QX200 ddPCR platform. (n=4-5/case). Cases with a major TSV-positive droplet population in the tumor tails tissue indicated the presence of satellite tumor cells. Our quality analysis showed DNA above the ddPCR threshold of detection was extracted from the tumor tails of 6 of 8 cases. The ddPCR assay showed that a TSV-positive droplet population was detected within the tumor tails in 5 of 6 cases, while 1 of 6 cases showed no such population in the tumor tails. Overall, our results indicates that t-NGS has potential for TSV detection within tumor tails. A prospective study is underway to further test its validity and compare it with standard histology. The project aims to improve surgical planning by ensuring removal of satellite tumor cells while lowering the risk of wound complications. Targeted gene-sequencing results of all cases within this study Case # Histology Pre-op Radiation DNA Extraction Successful TSV Probes (n) TSV+ Tumor TSV+ Tails TSV+ Normal 1 MFS N Y 5 4 4 0 2 MFS N Y 3 2 2 0 3 MFS Y Y* (normal insufficient) 3 3 0 N/A 4 UPS Y Y 3 2 0 1 5 MFS N Y 4 4 1 0 6 UPS N Y 3 3 3 1 7 MFS Y N N/A N/A N/A N/A 8 MFS Y N N/A N/A N/A N/A Citation Format: Miguel Alfonso V. Principe, Nalan Gokgoz, Patrick Prochazka, Peter C. Ferguson, Simin Dewji, Jay S. Wunder, Irene A. Andrulis, Brendan C. Dickson, Kim M. Tsoi. Detection of satellite tumor cells in peritumoral edema in myxofibrosarcoma and undifferentiated pleomorphic sarcoma using targeted gene sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5400.
Abstract 1002: Targeting adaptation to cancer treatment by drug combinations
Authors: Heping Wang, Augustin Luna, Gonghong Yan, Xubin Li, Ozgun Babur, Chris Sander, Gordon Mills
Journal: Cancer Research (2022)

Abstract Adaptation of tumors to therapeutic interventions contributes to dismal long-term patient outcomes. Adaptation to therapy involves the co-action of functionally related proteins that together activate cell survival programs and compensate for the therapeutic impact. Oncogenic dependencies to such adaptive events, however, can generate new therapeutic vulnerabilities that can be targeted with drug combinations. The precision medicine approaches in which targeted drugs are matched to pre-existing genomic aberrations fail to address the adaptive responses and resulting vulnerabilities. Here, we provide the mathematical formulation, implementation, and validation of the TargetScore method. The TargetScore identifies collective adaptive responses to targeted interventions as concurrent changes of phospho-proteins that are connected within a signaling network. Based on the adaptive responses, the method predicts drug-induced vulnerabilities. Using TargetScore, we inferred the adaptive responses with short-term (i.e., days) stress and long-term (i.e., months) acquired resistance to inhibitors of antiapoptotic mediators, MCL1 and BCL2. With experiments guided by the predictions, we identified synergistic interactions between inhibitors of PARP, SHP2, and MCL1 in breast cancer cells. TargetScore is readily applicable to existing precision oncology efforts by matching targeted drug combinations to emerging molecular signatures under therapeutic stress. Citation Format: Heping Wang, Augustin Luna, Gonghong Yan, Xubin Li, Ozgun Babur, Chris Sander, Gordon Mills. Targeting adaptation to cancer treatment by drug combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1002.
Abstract 341: Disruption of cellular crosstalk by blockage of ADAM17 inhibits tumor progression of pancreatic ductal adenocarcinoma
Authors: Hui-Ju Wen, Howard Crawford
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and will become the 2nd leading cause of cancer related death in the United States within the next 10 years. Lack of early symptoms and a poor response to current therapies make PDAC the deadliest of all major cancers. PDAC is characterized by a dense fibroinflammatory stroma which is composed of fibroblasts and immune cells and has been implicated to influence tumor progression and therapeutic outcome. In this study, we aim to disrupt cellular signaling pathways by targeting ADAM17 (a disintegrin and metalloprotease 17). ADAM17 is a membrane bound enzyme which cleaves cell surface proteins. Its function is closely linked with autocrine and paracrine signaling of immunomodulation as well as activation of EGFR, which is a central molecule for pancreatic tumorigenesis. To investigate whether EGFR is activated via a paracrine manner from macrophages, the most abundant immune-related stromal cells in pancreas cancers, we generated a pancreatic tumor mouse model with ADAM17 deletion in myeloid cells by using a dual recombinase strategy. We observed that lack of ADAM17 in the myeloid cells resulted in a delay of acinar cell transformation and an associated decrease in EGFR activation. To further examine the tumor supportive role of ADAM17, systemic inhibition of ADAM17 using anti-ADAM17 antibody, MEDI3622, was tested in orthotopic tumor bearing mice. Tumor regression was observed in the mice treated with MEDI3622 and was accompanied by high infiltration of cytotoxic T cells and low infiltration of G-MDSC (granulocytic myeloid-derived suppressor cells). In addition, activation of EGFR and STAT3, which are associated with two pro-tumoral signaling pathways, were reduced by MEDI3622. These results demonstrate a pronounced anti-tumor effect by ADAM17 blockage and indicate ADAM17 as a therapeutic target of pancreatic cancer. Citation Format: Hui-Ju Wen, Howard Crawford. Disruption of cellular crosstalk by blockage of ADAM17 inhibits tumor progression of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 341.
Mass Spectrometry Approaches Empowering Neuropeptide Discovery and Therapeutics
Authors: Krishna D. B. Anapindi, Elena V. Romanova, James W. Checco, Jonathan V. Sweedler
Journal: Pharmacological Reviews (2022)

The discovery of insulin in the early 1900s ushered in the era of research related to peptides acting as hormones and neuromodulators, among other regulatory roles. These essential gene products are found in all organisms, from the most primitive to the most evolved, and carry important biologic information that coordinates complex physiology and behavior; their misregulation has been implicated in a variety of diseases. The evolutionary origins of at least 30 neuropeptide signaling systems have been traced to the common ancestor of protostomes and deuterostomes. With the use of relevant animal models and modern technologies, we can gain mechanistic insight into orthologous and paralogous endogenous peptides and translate that knowledge into medically relevant insights and new treatments. Groundbreaking advances in medicine and basic science influence how signaling peptides are defined today. The precise mechanistic pathways for over 100 endogenous peptides in mammals are now known and have laid the foundation for multiple drug development pipelines. Peptide biologics have become valuable drugs due to their unique specificity and biologic activity, lack of toxic metabolites, and minimal undesirable interactions. This review outlines modern technologies that enable neuropeptide discovery and characterization, and highlights lessons from nature made possible by neuropeptide research in relevant animal models that is being adopted by the pharmaceutical industry. We conclude with a brief overview of approaches/strategies for effective development of peptides as drugs. <h3>Significance Statement</h3> Neuropeptides, an important class of cell-cell signaling molecules, are involved in maintaining a range of physiological functions. Since the discovery of insulin's activity, over 100 bioactive peptides and peptide analogs have been used as therapeutics. Because these are complex molecules not easily predicted from a genome and their activity can change with subtle chemical modifications, mass spectrometry (MS) has significantly empowered peptide discovery and characterization. This review highlights contributions of MS-based research towards the development of therapeutic peptides.